Opening of mitochondrial KATP channels enhances cardioprotection through the modulation of mitochondrial matrix volume, calcium accumulation, and respiration.

  title={Opening of mitochondrial KATP channels enhances cardioprotection through the modulation of mitochondrial matrix volume, calcium accumulation, and respiration.},
  author={Anthony J. Rousou and Maria Ericsson and Micheline Federman and Sidney Levitsky and James D. McCully},
  journal={American journal of physiology. Heart and circulatory physiology},
  volume={287 5},
Previously, we have shown that the pharmacological opening of the mitochondrial ATP-sensitive K channels with diazoxide (DZX) enhances the cardioprotection afforded by magnesium-supplemented potassium (K/Mg) cardioplegia. To determine the mechanisms involved in the cardioprotection afforded by K/Mg + DZX cardioplegia, rabbit hearts (n=24) were subjected to isolated Langendorff perfusion. Control hearts were perfused for 75 min. Global ischemia (GI) hearts were subjected to 30 min of equilibrium… 

Figures and Tables from this paper

CARDIAC Role of the Mitochondrial Ca2+ Transporters in the High-[K+]o Cardioprotection of Rat Hearts Under Ischemia and Reperfusion: A Mechano-Energetic Study

Mitochondria have a precise role for determining cardioprotection or stunning in high-K+ cardioplegic rat hearts under I/R, whereas known protective drugs increased the stunning of CPG-rat hearts and reduced muscle economy, whereas 5-hydroxydecanoate and Clzp together increasedThe stunning by inducing mitochondrial Ca2+ overload.

Relationship Between Mitochondrial Matrix Volume and Cellular Volume in Response to Stress and the Role of ATP-Sensitive Potassium Channel

5-Hydroxydecanoate reduced mitochondrial volume during exposure to both stresses with DZX, supporting a role for a mitochondrial ATP-sensitive potassium channel in the mechanism of cardioprotection by DZX.

Acetaminophen-mediated cardioprotection via inhibition of the mitochondrial permeability transition pore-induced apoptotic pathway.

Data suggest that acetaminophen mediates cardioprotection, in part, via inhibition of the mitochondrial permeability transition pore and subsequent apoptotic pathway, as well as electron micrograph analysis, suggest.

Effect of diazoxide and Ca2+ on rat heart mitochondria loaded with Na+

It was found that ischemia and followed reperfusion decreased diastolic and systolic pressure in an isolated rat heart and damaged membranes of mitochondria and sarcoplasmic reticulum and the effect of diazoxide and Ca 2+ on isolated ratheart mitochondria loaded with Na + was studied.

Modulation of mitochondrial respiratory function and ROS production by novel benzopyran analogues.

In isolated rat heart mitochondria, the novel benzopyran analogues act as protonophoric uncouplers of oxidative phosphorylation and decrease the generation of reactive oxygen species in a dose-dependent manner.



Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection.

The profile of activity of diazoxide (and perhaps KATP openers in general) suggests that they protect ischemic hearts in a manner that is consistent with an interaction with mitochondrial KatP.

Mitochondrial ATP-Sensitive Potassium Channels Attenuate Matrix Ca2+ Overload During Simulated Ischemia and Reperfusion

Rhod-2 fluorescence in adult rabbit ventricular cardiomyocytes was measured as an index of mitochondrial matrix Ca2+ concentration ([Ca2+]m), using time-lapse confocal microscopy, and inhibitors of the mitochondrial permeability transition (MPT), cyclosporin A and bongkrekic acid did not alter [Ca2 +]m accumulation during ischemia, but markedly suppressed the accumulation during reperfusion.

Do Modulators of the Mitochondrial KATP Channel Change the Function of Mitochondria in Situ?*

At a cardioprotective dose, the main functional effect of diazoxide depends on respiratory substrates and seems not to be related to KATP channel activity.

The effects of ischaemic preconditioning, diazoxide and 5‐hydroxydecanoate on rat heart mitochondrial volume and respiration

In isolated mitochondria, 5HD was rapidly converted to 5HD‐CoA by mitochondrial fatty acyl CoA synthetase and acted as a weak substrate or inhibitor of respiration depending on the conditions employed and highlighted the dangers of using 5HD and diazoxide as specific modulators of mitoKATP channels in the heart.

Selective opening of mitochondrial ATP-sensitive potassium channels during surgically induced myocardial ischemia decreases necrosis and apoptosis.

Mitochondrial ATP-Sensitive Potassium Channels Attenuate Matrix Ca2+ Overload During Simulated Ischemia and Reperfusion: Possible Mechanism of Cardioprotection

The hypothesis that attenuation of mitochondrial Ca2+ overload, as a consequence of partial mitochondrial membrane depolarization by mitoKATP channels, underlies cardioprotection is supported.

Bioenergetic consequences of opening the ATP-sensitive K(+) channel of heart mitochondria.

Opening mitochondrial K(ATP) channels has little direct effect on respiration, membrane potential, or Ca(2+) uptake but has important effects on matrix and intermembrane space volumes.

Amelioration of ischemic calcium overload correlates with high-energy phosphates in senescent myocardium.

K-Mg cardioplegia is correlated with amelioration of [Ca2+]i accumulation during ischemia and preservation of left ventricular function after reperfusion and suggest that optimal functional recovery from surgically induced ischemian recovery is provided by K-MmgCardiopleGia in the aged myocardium.

Opening of Mitochondrial K+ Channels Increases Ischemic ATP Levels by Preventing Hydrolysis

The results suggest that mitoKATP-mediated protection occurs due to selective inhibition of mitochondrial ATP hydrolysis during ischemia, without affecting ATP synthesis after reperfusion.